- “feed-or-breed” responses -including mating rituals, and sexual activity -cardiac & smooth muscle, gland cells, nerve terminals

Autonomic Drugs Flashcards by EDGAR JORDAN ESPINOLA

Nervous system is divided into:

1- CNS central nervous system, brain & spinal cord
2- PNS, peripheral nervous system, neuronal tissues outside the CNS

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Autonomic Nervous System (ANS)

-is largely independent (autonomous) in that its activities are not under direct conscious control
-concerned primarily with control & integration of visceral functions necessary for life such as cardiac output, blood flow distribution, & digestion

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in the nervous system, chemical transmission occurs b/w:

-nerve cells, & b/w nerve cells & their effector cells

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Autonomic Nervous System: 2 major parts

1- Sympathetic (thoracolumbar)
2- Parasympathetic (craniosacral)

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parasympathetic

“feed-or-breed” responses
-including mating rituals, and sexual activity
-cardiac & smooth muscle, gland cells, nerve terminals

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sympathetic

-“flight-or-fight” response
-includes releasing stress hormones, regulating the metabolism of cells, and generally maintaining homeostasis
-sweat glands, renal vascular smooth muscle

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Somatic

skeletal muscle

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most thoracic & lumbar sympathetic preganglionic fibers are:

-short & terminate in ganglia located in the PARAvertebral chains that lie on either side of the spinal column

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most of the remaining sympathetic preganglionic fibers are:

-somewhat long & terminate in PREvertebral ganglia, w/c lie in front of the vertebrae

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post ganglionic sympathetic fibers:

-from the ganglia,
-run to the tissues innervated

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some preganglionic Parasympathetic fibers:

-terminate in parasympathetic ganglia located outside the organs innervated:

-Ciliary, Pterygopalatine, Submandibular, & Otic Ganglia

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several Pelvic Ganglia:

-are innervated by sacral preganglionic nerves that are similar to sympathetic preganglionic fibers

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Are anatomic designations & do not depend on the type of transmitter released from the nerve endings nor the kind of effect evoked by nerve activity

1- sympathetic
2- parasympathetic

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effects evoked by nerve activity

1- Excitatory
2- Inhibitory

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Enteric Nervous System (ENS)

-is a largely & highly organized collection of neurons located in the walls of the gastrointestinal (GI) system
-over 150M neurons
-sometimes considered as the 3rd division of Autonomic Nervous System (ANS)
-involved on both motor & secretory activities of the gut

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the Enteric Nervous System includes:

1- Myenteric plexus (Auerbach)
2- Submucous plexus (Meissner)

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Enteric Nervous System functions in a:

-semiautonomous manner

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Acetylcholine (ACh)

-primary transmitter at the ANS ganglia
-primary excitatory transmitter to smooth muscle & secretory cells in the ENS
-probably also a major neuron to neuron (ganglionic) transmitter in the ENS

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Adenosine triphosphate (ATP)

-acts as a transmitter or cotransmitter at many ANS-effector synapses

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Calcitonin gene-related peptide (CGRP)

-found w/ substance P in cardiovascular sensory nerve fibers
-present in some secretomotor ENS neurons & interneurons
-a cardiac stimulant

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Cholecystokinin (CKK)

-may act as a cotrtansmitter in some excitatory neuromuscular ENS neurons

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Dopamine

-a modulatory transmitter in some ganglia & the ENS
-possibly a postganglionic sympathetic transmitter in renal blood vessels

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Enkephalin & related Opioid peptides

-present in some secretomotor & interneurons in the ENS
-appear to inhibit ACh release & thereby inhibit peristalsis
-may stimulate secretion

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Peristalsis

-the involuntary contraction and relaxation of longitudinal and circular muscles throughout the digestive tract

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Galanin

-present in secretomotor neurons -may play a role in appetite-satiety mechanisms

GABA (gamma aminobutyric acid)

-may have presynaptic effects on excitatory ENS nerve terminals -have some relaxant effect on the gut -probably not a major transmitter in the ENS

Gastrin Releasing Peptide (GRP)

-extremely potent excitatory transmitter to gastrin cells -aka mammalian bombesin

Neuropeptide Y (NPY)

-found in many noradrenergic neurons -present in some secretomotor neurons in the ENS & may inhibit secretion of water & electrolytes by the gut -causes long lasting vasoconstriction -also a cotransmitter in some parasympathetic postganglionic neurons

Nitric Oxide (NO)

-a cotransmitter at inhibitory ENS & other neuromuscular junctions, -may be especially important at sphincters, -cholinergic nerves innervating blood vessels appear to activate the synthesis of NO by vascular endothelium, -NO is not stored, it is synthesized on demand by Nitric Oxide Synthase (NOS)

Norepinephrine (NE)

-primary transmitter at most sympathetic postganglionic nerve endings

Serotonin (5-HT)

-an important transmitter or cotransmitter at excitatory neuron-to-neuron junctions in the ENS

Substance P

-an important sensory neurotransmitter in the ENS and elsewhere, -is a vasodilator (probably via the release of Nitric Oxide)

tachykinins

-appear to be excitatory cotransmitters w/ ACh at ENS neuromascular junctions

Cholinergic

-they work by releasing acetylcholine, -almost all efferent fibers leaving the CNS, -most parasympathetic postganglionic & some sympathetic postganglionic fibers

Noradrenergic

-often called simply adrenergic -release norepinephrine or noradrenaline

5 key features of neurotransmitters functions provide potential targets for pharmacologic therapy:

1- synthesis 2- storage 3- release 4- termination of action of the transmitter 5- receptor effects

large vesicles contain

-a high concentration of peptide cotransmitters

smaller vesicles contain

most of the acetylcholine

VAMP vesicle-associated membrane proteins

serve to align vesicles with release sites on the inner neuronal cell membrane & participate in triggering the release of transmitter

Synaptosomal nerve-associated proteins SNAP's

-interacts with VAMP's

fusion proteins

vamp's & snap's are collectively called

Acetylcholine is synthesized

-in the cytoplasm from acetyl CoA & choline through the catalytic action of enzyme Choline Acetyltransferase (ChAT)

Acetyl CoA is synthesized

-in mitochondria

Choline Transporter (CHT)

-Choline is transported by a sodium dependent membrane

this symporter (CHT) can be blocked by a group of research drugs called

hemicholiniums

once synthesized, acetylcholine is transported from the cytoplasm into the vesicles by, driven by proton efflux

-a vesicle-associated transporter (VAT)

this antiporter can (VAT) can be blocked by the research drug

Vesamicol

most of the vesicular acetylcholine (a positively charged quaternary amine) is bound to negatively charged

vesicular proteoglycan (VPG)

vesicles are concentrated on the inner surface of the nerve terminal facing the synapse through the interaction of so-called SNARE PROTEINS on the vesicle

- a subgroup of VAMP's called v-SNAREs, especially SYNAPTOBREVIN

SNAP's called t-SNAREs

-Syntaxin & SNAP-25

the acetylcholine release process is blocked by

botulinum toxin through the enzymatic cleavage of 2 amino acids from 1 or more of the fusion proteins

acetylcholine molecules may bind to & activate an acetylcholine receptor

cholinoceptor

eventually, & usually very rapidly, all of the acetylcholine released diffuses within range of an,

acetylcholinesterase (AChE)

AChE very efficiently splits acetylcholine into

choline & acetate

richly supplied with acetylcholinesterase

cholinergic synapses

the half-life of acetylcholine molecules in the synapse is therefore very short

a fraction of a second

acetylcholinesterase is also found in other tissues

red blood cells

other cholinesterases w/ lower specificity for acetylcholine including

butyrylcholinesterase (pseudocholinesterase) are found in blood plasma, liver, glia, and many other tissues

transport the precursor amino acid tyrosine into the nerve ending, convert it to dopa, & then synthesize catecholamine transmitter

adrenergic neurons

catecholamine transmitter

dopamine, norepinephrine or epinephrine

final product in most sympathetic postganglionic neurons

norepinephrine

in adrenal medulla & certain areas of the brain, some norepinephrine is further converted into

epinephrine

in dopaminergic neurons, synthesis terminates with

dopamine

converts tyrosine to dopa

tyrosine hydroxylase

the rate limiting step in catecholamine transmitter synthesis

conversion of tyrosine to dopa

tyrosine hydroxylase can be inhibited by the tyrosine analog

metyrosine (a-methyltyrosine)

a high affinity antiporter for the catecholamines located in the wall of storage vesicle

vesicular monoamine transporter (VMAT)

-VMAT can be inhibited by, -cause depletion of transmitter stores

reserpine alkaloids (tetrabenazine, deutetrabenazine)

transporter that carries norepinephrine & similar molecules back into the cell cytoplasm from the synaptic cleft

Norepinephrine Transporter (NET)

also commonly called uptake 1 or reuptake 1 & is partially responsible for the termination of synaptic activity

NET

NET can be inhibited by

Cocaine & certain antidepressant drugs resulting in an increase of transmitter activity in the synaptic cleft

in addition to primary transmitter (norepinephrine) are simultaneously released from the same vesicles

adenosine triphosphate (ATP), dopamine -B- hydroxylase and peptide cotransmitters

-indirectly acting & mixed action sympathomimetics, -are capable of releasing stored transmitter from noradrenergic nerve endings by a calcium-dependent process -poor agonists (some are inactive) at adrenoceptors, but are excellent substrates for monoamine transporters

tyramine amphetamines ephedrine

the most important families of transport proteins

ABC (ATP binding cassette) SLC (solute carrier)

use ATP for transport

ABC

-are cotransporters, -in most cases, use the movement of sodium as energy source -also transport transmitters in the reverse direction in a sodium independent fashion

SLC proteins

-norepinephrine transporter, -member of the SLC family

NET, SLC6A2

SLC6A

DAT

SLC6A4

SERT

in the CNS, they are important targets of several antidepressant drug class

NET & SERT

the most important inhibitory transmitter in the CNS, is the substrate for at least 3 SLC transporters

GABA, Y-aminobutyric acid

3 SLC transporters

GAT1 GAT2 GAt3

the target of an antiseizure medcation

GAT1

other SLC proteins transport

glutamate, the major excitatory CNS transmitter

measurement of total metabolites in a 24H urine sample

VMA & metanephrines

termination of noradrenergic transmission results from 2 processes:

1- simple diffusion away from the receptor site (w/ eventual metabolism in the plasma or liver) 2-reuptake into the nerve terminal by NET or into perisynaptic glia or other cells

metabolism of catecholamines by

(COMT) catechol-O-methyltransferase & (MAO) monoamine oxidase

primary acetylcholine receptor subtypes

muscarinic nicotinic

widely used to describe receptors that respond to catecholamines such as norepinephrine

adrenoceptor

denotes receptors (both muscarinic and nicotinic) that respond to acetylcholine

cholinoceptor

Cholinoceptors

Muscarinic M1, M2, M3, M4, M5 Nicotinic Nn, Nm

Adrenoceptors

Alpha 1 Alpha2 Beta1 Beta2 Beta3

Dopamine receptors

D1 (DA1), D5 D2 (DA2) D3 D4

the general class of adrenoceptors can be further subdivided into

*a- adrenoceptor *b-adrenoceptor *dopamine receptor

autonomic effector tissues

gut, airways, bladder

NANC

NonAdrenergic, NonCholinergic neurons

a neurotoxin derived from chili peppers can cause the release of transmitter (substance P) from such neurons, & if given in high doses- destruction of the neurons

capsaicin

-CNS neurons, sympathetic postganglonic neurons, some presynaptic sites -formation of IP3, & DAG, increased intracellular calcium

Muscarinic M1

-myocardium, smooth muscle, some presynaptic sites, CNS neurons -opening of potassium channels, inhibition of adenylyl cyclase

Muscarinic M2

-Exocrine glands, vessels (smooth muscle & endothelium), CNS neurons -like M1, receptor ligand binding

Muscarinic M3

-CNS neurons, possibly vagal nerve endings -like M2, receptor ligand bindng

Muscarinic M4

-Vascular endothelium, especially cerebral vessels, CNS neurons -like M1, receptor ligand binding

Muscarinic M5

-postganglionic neurons, some presynaptic cholinergic terminals, pentameric receptors typically contains a & b type subunits only -opening of sodium, potassium channels, depolarization

Nicotinic Nn (neuronal nicotinic)

-Skeletal muscle neuromuscular end plates, receptors typically contain 2 a1 & b1 type subunits in addition to G & D subunits

Nicotinic Nm

-postsynaptic effector cells, especially smooth muscle -formation of IP3, & DAG, increased intracellular calcium

Alpha1

presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle -inhibition of adenylyl cyclase, decreased cAMP

Alpha2

-postsynaptic effector cells, especially heart, lipocytes, brain, presynaptic adrenergic & cholinergic nerve terminals, juxtaglomerular apparatus of renal tubules, ciliary body epithelium -stimulation of adenylyl cyclase, increased cAMP

Beta1

-postsynaptic effector cells, especially smooth muscle & cardiac muscle -stimulation of adenylyl cyclase & increased cAMP, activates cardiac Gi under some conditions

Beta2

-postsynaptic effector cells especially lipocytes, heart -stimulation of adenylyl cyclase, increased cAMP

Beta3

-brain, effector tissues, especially smooth muscle of the renal vascular bed -stimulation of adenylyl cyclase & increased cAMP

D1 (DA1), D5

-brain, effector tissues especially smooth muscle, presynaptic nerve terminals -inhibition of adenylyl cyclase, increased potassium conductance

D2 (DA2)

-brain -inhibition of adenylyl cyclase

-brain, cardiovascular system -inhibition of adenylyl cyclase

the sensory fibers of nonadrenergic, noncholinergic systems are probably better termed as

sensory efferent or sensory local effector

potent agonists in many autonomic effector tissues

peptides

particularly important in the responses of the ANS to the administration of autonomic drugs

negative feedback

parasympathetic system leading to growth, used to rest and digest

trophotropic

sympathetic system leading to energy expenditure which is activated for fight or flight

ergotropic

presynaptic receptors that respond to the primary transmitter substance released by the nerve ending are called

autoreceptors

may be activated by substances released from other nerve terminals that synapse with the nerve ending

heteroreceptors

an extreme form of up-regulation occurs after denervation of some tissues resulting in

denervation supersensitivity

-resulting fast -evokes a propagated action potential if threshold is reached

excitatory postsynaptic potential (EPSP)